1. Field of the Invention
The present invention relates to the use of pervanadate as a potent inhibitor of phosphotyrosine phosphatase with a distinct specificity from previously described inhibitors.
This invention also relates to the use of such a particular property and specification of pervanadate provide a potentially useful agent for regulation of cell growth.
2. Brief Description of the Prior Art
Vanadate on the one hand, and hydrogen peroxide (H.sub.2 O.sub.2) on the other hand, are well documented to mimic the actions of insulin. Recent interest in vanadate has increased since it has been demonstrated to increase the tyrosine kinase activity of the insulin receptor (Tamura et al., J. Biol. Chem. 259, 6650-6658, 1984), and it has been used successfully in short-term treatment of streptozotocin-induced diabetic rats (Heyliger et al., Science 227, 1474-1477, 1985; Meyerovitch et al., J. Biol Chem. 262, 6658-6662, 1987). It has also been demonstrated that a mixture of vanadate and H.sub.2 O.sub.2 produced a synergistic effect to augment IGF-II (insulin-like growth factor II) binding to rat adipocytes and to activate the insulin receptor kinase (Kadota et al., J. Biol. Chem. 262, 8252-8256 1987).
The efficacies of the mixture of vanadate and H.sub.2 O.sub.2, of each agent alone, and of insulin to increase IGF-II binding have proved to be correlated with their respective efficacies to activate the insulin receptor tyrosine kinase in an in situ intact cell assay (Kadota et al., Supra). It has also been demonstrated that the synergistic insulin-like effect of vanadate mixed with H.sub.2 O.sub.2 was due to the generation of peroxide(s) of vanadate which are termed pervanadate (Kadota et al., Biochem. Biophys. Res. Commun 147, 259-266, 1987). In this study, it has also been disclosed that addition of catalase abolishes the synergism only if it is made at the same time as the vanadate and H.sub.2 O.sub.2. However, such an addition does not abolish the synergism 10 min. after mixing of the two agents. It is disclosed that pervanadate stimulates in situ tyrosine phosphorylation of the insulin receptor in adipocytes with maximal effects similar to that of insulin. Concomitant with enhanced tyrosine phosphorylation, pervanadate activates the insulin receptor kinase but with a slower time course than insulin.
The inbibition of insulin receptor .beta.-subunit tyrosine dephosphorylation by pervanadate and lack of in vitro stimulation of autophosphorylation or tyrosine kinase activity suggest that this insulin-mimetic agent acts via inhibition of specific tyrosine phosphatase(s).